Various medicament (drug) solutions are commonly administered intravenously (via IV) from sterile containers to patients. Oftentimes, such solutions comprise a mixed combination of a liquid diluent, e.g., an aqueous dextrose or NaCl solution, and a liquid medicament. Desirably, the medicament and diluent are stored separately in the container under aseptic conditions and are not mixed together until immediately prior to use so as to prevent degradation of the final product. Common packaging of the diluent and medicament is often further complicated by the character of the medicament which may be in liquid form and, thus, susceptible to hydraulic pressure on the container, as well as degradation under light or oxygen exposure.
Accordingly, various such medicaments which become unstable with time in solution have typically been separately stored in gas-impermeable vials, containers, or the like prior to their use. Before being administered to a patient, medicaments stored in this fashion must be mixed, or diluted in, a physiological solutions or diluents which are also preserved separately. While able to maintain medicament sterility and effectiveness, separate component storage is cumbersome and involves the risk of bacteriological contamination during handling, mixing, and subsequent administration to a patient. Accordingly, medical containers have been developed which include compartments for storing unstable medicaments and compartments which contain diluent liquids. Immediately prior to IV administration to a patient, the components are placed in communication with one another so that the contents can be mixed together aseptically.
Multiple compartment containers, which allow separate storage of diluents and medicaments are known. Such containers are disclosed, for example, in U.S. Pat. No. 4,608,043 to Larkin, U.S. Pat. No. 5,176,634 to Smith et al. and U.S. Pat. No. 5,462,526 to Barney et al. U.S. Pat. Nos. 4,608,043, 5,176,634 and 5,462,526 are expressly incorporated herein in their entirety by reference. The compartments of the containers disclosed in the foregoing patents are separated from one another by peelable or frangible heat seals. The seals are ruptured by manipulation of the container so that the contents of the compartments can be mixed together to thereby form a solution which is delivered to the patient through a standard IV arrangement.
Solution containers on the market today are generally manufactured of materials comprising PVC plastic. PVC material is generally quite murky in aspect, making it difficult to inspect the contents of a container manufactured of such material. Consequently, inspecting such containers for leaks and moisture contamination is quite difficult, as is verifying whether complete mixing of the medicament and diluent has taken place prior to administration to a patient. In addition, various hazardous chemicals are used in the manufacture of PVC material which must be disposed of in an environmentally safe manner. PVC containers must be carefully disposed of following their use, because PVC emits a toxic gas when incinerated and includes a toxic plasticizer that can leach into the surrounding environment if the container is buried in a landfill. This toxic plasticizer is also able to leach into IV solutions, making PVC containers unsuitable for use with several types of drugs, particularly liquid drugs.
The medicament compartment of such multi-compartment containers is desirably protected from atmospheric gasses as well as from exposure to UV and ambient radiation in order to avoid degradation of the medication contained therein. One known method of protecting the medicament compartment from, for example, moisture and oxygen contamination is disclosed in U.S. Pat. No. 5,267,646 to Inouye, et al., in which the medicament compartment is surrounded by a secondary compartment containing a desiccant and an oxygen absorber. Free oxygen and moisture vapor is allowed to penetrate the material of the secondary compartment and is absorbed by the desiccant and oxygen scrubber before it is able to effect the medicament. Although this method is able to provide some degree of protection for the medicament compartment against free oxygen and water vapor, the method requires an additional layer of material (a secondary compartment) to be provided around the medicament, making it more difficult to inspect the contents of the medicament container prior to reconstitution. Moreover, no protection is provided against the effects of UV or ambient light degradation of the contents of the medicament compartment.
U.S. Pat. No. 5,176,634 to Smith et al., discloses a medical container having multiple compartments separated by peelable seals which may be ruptured by manually applying pressure to the exterior of the container. The container is formed of two sheets of flexible materials which are sealed together along their perimeter. Separate diluent and medicament compartments are formed in the container by frangible heat seals which span the sides of the container and, thus, divided into separate compartments. The rear sheet is impermeable to water vapor and is constructed of a laminated material having an inner layer of polypropylene, a middle layer of aluminum foil and an outer layer of polyester film. Vapor impermeability of the rear sheet extends the shelf life of the product by reducing, by half, the permeation of diluent vapor from the container, and the permeation of vapor from the atmosphere into the medicament compartment. Additional reduction and vapor permeability is provided for the medicament compartment by peelably affixing a third sheet of laminated material, which is identical to the rear sheet, over the container front sheet in the region of the medicament compartment. This third sheet of laminated material is sized to cover the medicament compartment and, in combination with the rear sheet, forms a vapor impermeable enclosure which surrounds the medicament compartment.
However, once the vapor impermeable third sheet is peeled-away from the medicament compartment, the medicament compartment is no longer enclosed and is, therefore, susceptible to vapor permeation from the atmosphere. In addition, diluent vapor is able to migrate from the diluent compartment into the medicament compartment through the material of the peelable seal which separates them. Because the vapor impermeable covering is routinely peeled-away from the medicament compartment during a hospital's incoming inspection procedure, long term storage of such containers is problematic. In cases where the medicament is a liquid, and highly susceptible to degradation by water vapor, the shelf life of a container that has had its vapor impermeable covering removed is often no more than a few days.
Containers developed for binary combinations of liquid medicaments and liquid diluents are also quite susceptible to internal hydrostatic pressure developed by squeezing the container or by an impact such as might be caused by dropping the container onto a hard surface. When this internal hydrostatic pressure develops, the peelable or frangible seals which separate the diluent and medicament compartments, or the seal which separates the medicament from the outlet compartment may inadvertently peel-open, causing either premature mixing of the container's binary components, or cause a bolus of liquid medicament to enter the outlet compartment.
In various prior art multiple compartment containers, simple frangible or peelable seals are used to divide medicament and diluent compartments to preclude inadvertent delivery of any of the components prior to mixing. Such simple seals are formed across the container in its width direction, and have a generally uniform cross-sectional thickness and length throughout the entire seal. When the container is manipulated in order to rupture the seals, and thereby mix the medicament and diluent together prior to delivery, the mechanical pressure of the liquid diluent against a seal is relieved as soon as any portion of the seal ruptures. The diluent is then allowed to enter the medicament compartment. Such a partial rupture of a linear seal often does not allow complete delivery of the fluid contents of the diluent compartment to the medicament. Significant quantities of diluent may remain in the diluent compartment, trapped in the corners defined by the sidewall of the compartment and the left and right ends of the seal. Such partial rupture may also result in incomplete mixing of medicaments with diluents and incomplete delivery of the mixed product to the patient.
In addition, in the case where the medicament is a liquid, the peelable seal separating the liquid medicament from an outlet compartment may preferentially rupture before the seal separating the liquid medicament from the diluent compartment. An undiluted portion of liquid medicament may thus be present in the outlet compartment when the set port is pierced by an IV set drug spike, allowing a bolus of relatively undilute medicament to enter the IV line to a patients The danger to a patient in this circumstance cannot be minimized.
It is therefore desirable to provide an IV container having multiple compartments for storage of liquid diluents and medicaments in a single package to have peelable seals dividing the compartments which are configured to be substantially completely ruptured along their entire length for complete combination and mixing of the contents, and to be preferentially rupturable between the medicament and diluent compartments to ensure that the container's binary components are substantially mixed before the seal leading to the outlet compartment is ruptured. Such a seal configuration would assure delivery of the total quantity of the final mixed product while minimizing the potential for medicament bolus formation. It is thus desirable that the container arrangement preclude the inadvertent delivery of any of the components prior to mixing, but in the event of improper mechanical manipulation of the container, the container arrangement must preclude the inadvertent delivery of undiluted liquid medicament. The container should further allow verification of the condition of the components following receipt of the container by a hospital's pharmaceutical services, but prior to storage and subsequent dispensing.
In certain cases where the diluent is an active pharmaceutical component of a binary mixture, such as for emulsions, liposomes, and the like, it is further desirable that the container be entirely filled with the liquid, such that there is no gaseous head-space remaining in the diluent compartment. Emulsions and liposomes, for example, are particularly susceptible to sloshing which can degrade the substances to the point of ineffectivity.
When containers are filled with these materials, the formed film web is commonly blown-open with a jet of dry nitrogen or filtered air to define a volume into which a measured amount of liquid is introduced. Oftentimes the liquid volume contained in such a container must be controlled to within about 1 part in 100. It is extremely difficult to vent the filtered air or nitrogen from the container after the container is filled with a liquid. The container walls must be slowly squeezed until the air is vented through the fill port but before any of the liquid escapes.
While effective to a certain degree, such a method of minimizing gaseous head-space in a container adds a significant amount of time to the filling process with a consequent reduction in the final product volume. In addition, the filling apparatus must include an additional step (the head-space removal step) as well as additional costly and complex apparatus to effect the step.
It is therefore desirable that the container be manufactured and filled in such a manner that the head-spaced formed during the filling step may be substantially removed in the final product without the addition of a processing step or separate apparatus.